Method and apparatus for transcutaneous infusion of carbon dioxide for local relief of pain and other ailments

ABSTRACT

The invention relates to methods and devices for transcutaneous and transmucosal application of carbon dioxide in the form of a gas and in the form of a capnic solution (such as carbonated water) for the relief of pain, including musculoskeletal disorders, neuralgias, rhinitis and other ailments. Gaseous carbon dioxide is applied to the skin for at least three minutes, and the capnic solution may be held on the skin for at least three minutes, which provides relief of symptoms. The capnic solution may also be sprayed onto mucous membranes such as the nose for relief of symptoms such as allergic rhinitis.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional PatentApplication No. 60/185,495, filed on Feb. 28, 2000, which isincorporated by reference herein.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates to methods and apparatus for delivery ofcarbon dioxide (CO₂), and other physiologically active agents toindividuals.

[0004] Alternative methods and devices for delivering carbon dioxide andother gases to individuals are described in U.S. patent application Ser.No. 09/614,389 filed Jul. 12, 2000 and 09/708,186 filed Nov. 7, 2000,which are incorporated by reference herein. Those applications describethe use of C0 ₂, or other therapeutic gas or agents, and associatedtransmucosal dispensing apparatus for providing controlled amounts ofgas to the nose, mouth and/or eye for use in the relief of headaches,allergic rhinitis and asthma, among other ailments, and for thepotentiation of the actions of certain drugs and/or physiologicallyactive agents.

[0005] The present invention, however, relates to methods and apparatusfor transcutaneous application of C0 ₂ (i.e., applied to the skin) andtransmucosal application of C0 ₂ (i.e., applied to a mucous membrane) inboth the form of a gas and in the form of aqueous solutions (such ascarbonated water).

[0006] 2. Related Art

[0007] Subcutaneous Applications of C0 ₂

[0008] C0 ₂ is a known therapeutic agent and subcutaneous applicationhas been found to relieve a variety of ailments.

[0009] A West German group conducted a 3-year clinical treatment programinvolving local subcutaneous injection of gaseous C0 ₂ [A. Grosshans andH. Gensch, Z. gesamte inn. Med., Jahrig. 42 (1987) Heft 23]. The 335patients treated had the following indications:

[0010] 1. Cervico-cranial syndrome, in particular pains in the neck,contractions of the neck, headache including migraine and vertigo;

[0011] 2. Cervico-brachial syndrome;

[0012] 3. Lumbalgia with and without root-irritation syndrome;

[0013] 4. Other muscular-skeletal pain conditions (degenerative changes,muscular contractions and others).

[0014] The treatments consisted of daily or twice-weekly injections of100-200 ml of C0 ₂ gas under the skin, in the body regions indicated,for a period of 2-5 weeks (10-15 injections). An ˜8 cm diameter gasemphysemum arose with a mild hyperemia of the skin at the injection sitewhich disappeared within 3-5 minutes after the injection. Improvement ofthe indicated disorder occurred after 4-5 treatments. Of the totalpatients treated, 171 became difficulty-free or were substantiallyimproved, 157 were improved with some remaining distress and 7 had noimprovement.

[0015] Mineral Baths

[0016] Effervescent mineral water baths have been known from antiquityto the present as being effective for relieving musculoskeletal, neuraland rheumatic pain. In general, it has been assumed that the dissolvedmineral components were responsible for the therapeutic effects of thebaths. However, the experimental evidence developed by the inventorssuggests that the effectiveness of such baths arises from the high C0 ₂content of the mineral water rather than from its other dissolvedcomponents.

SUMMARY OF THE INVENTION

[0017] The inventors discovered that results similar to those obtainedby subcutaneous injection of C0 ₂ could be obtained by transcutaneousapplication of C0 ₂. This application could be made either by applyingthe C0 ₂ in the form of gas, or alternatively, in the form of aqueoussolutions (i.e., carbonated water).

[0018] Application of the C0 ₂ may be transcutaneous (through the skin)or transmucosal (through a mucous membrane). For example, gaseous C0 ₂or an aqueous solution of CO₂ may be applied to external skin surfacesfor relief of various ailments. Furthermore, an aqueous solution of C0 ₂may be sprayed into the nose, mouth and/or upper respiratory passagesfor relief of various ailments as an alternative to the application ofgaseous C0 ₂ which was described in U.S. patent applications Ser. No.09/614,389 and 09/708,186.

BRIEF DESCRIPTION OF THE DRAWINGS

[0019]FIG. 1 shows a device used to test absorption of carbon dioxide.

[0020]FIG. 2 shows the carbon dioxide absorbed by a wet paper towel inan experiment using the device of FIG. 1.

[0021]FIG. 3 shows the device of FIG. 1 used on a human subject.

[0022]FIG. 4 shows a device for applying carbonated water to a selectedportion of a subject's external skin surface.

[0023]FIG. 5 shows a subject utilizing a spray bottle containingcarbonated water.

[0024]FIG. 6 shows a device used for obtaining a quantitativemeasurement of absorption of carbon dioxide in carbonated water throughthe skin of a human subject.

[0025]FIG. 7 shows the results of an experiment using the device of FIG.6.

[0026]FIG. 8 shows the results of the same experiment as in FIG. 7, buttaken immediately after the subject had been exercising.

[0027]FIG. 9 shows the results of the experiment of FIG. 8 fifteenminutes after the measurements shown in FIG. 8.

[0028]FIG. 10 shows a therapeutic application of gaseous carbon dioxideto an affected area of a subject.

[0029]FIG. 11 shows another therapeutic application of gaseous carbondioxide to an affected area of a subject using a cup device.

[0030]FIG. 12 shows a subject submerging an affected body part intocarbonated water.

[0031]FIG. 13 shows embodiments of “patches” for application of liquidor gaseous C0 ₂.

DETAILED DESCRIPTION OF THE DRAWINGS

[0032] Transcutaneous application of gaseous C0 ₂ has been found torelieve ailments previously treatable by subcutaneous injections ofgaseous C0 ₂.

[0033] Application of Gaseous C0 ₂

[0034] One of the inventors undertook tests between Jan. 3 and Feb. 6,2000 to determine whether beneficial results obtained by subcutaneousinjection of C0 ₂ could be obtained by the less invasive means oftranscutaneous diffusion. Since the above-cited subcutaneous treatmentsoccurred over periods of days to weeks, the inventor reasoned thatcontinuous chronic infusion, via a transcutaneous “CO₂ patch”, mightgive equivalent relief of distress if the period of the 100-200 ml doseinfusion was applied over 24 hours or more, i.e., at a rate as low as˜0.1 mil/minute.

[0035] To determine the inherent rate of absorption and diffusion of C0₂ in a “passive” aqueous medium a preliminary in vitro experiment wasperformed. The apparatus and method employed for measuring the rate ofC0 ₂ absorption by a surface is illustrated in FIG. 1. The device wasplaced on a table top 150, and comprised a source of C0 ₂ in the form ofa cylinder 101 and a flow regulator 110, including a pressure regulator112 and flow meter 113. Polyethylene tubing 115 of approximately 0.2 cm²lumen connected the cylinder 101 to a glass funnel 120 having a maximumarea of 80 cm². An additional length of tubing 125 was used formeasurement of changes in gas volume. This gas volume measurement meansused in the experiment could be eliminated in a device intended toadminister C0 ₂ to a patient's skin surface. The entire system waspurged of air by prolonged C0 ₂ flow. The additional length of tubing125 was purged first, then a bolus of low-volatility (forepump) oil 130was inserted into its open end and the end plugged. The funnel 120 wasthen purged with its open end resting on a portion of the selected testsurface 140 immediately adjacent to the portion to be tested, and withthe purge flow escaping at its edge. At zero time the purge flow wasterminated, the plug in the tube 125 end was removed and the funnel wasslid onto the test portion of the surface without breaking the sealbetween the funnel edge and the wet surface. The displacement of the oilbolus 130 within the 0.20 cm² lumen of the tube 125 was then observed asC0 ₂ gas was removed from the closed system via absorption in thesurface 140; i.e., each cm of displacement corresponded to absorption of0.20 cc of gas by 80 cm² of test surface.

[0036] As a control, the system was first tested by placing the funnel120 on a non-absorbing test surface 140 without water. No movement ofthe bolus 130 occurred, which indicated that there was no significantabsorption or evolution of gas within the system.

[0037] Next, the funnel was placed on test surface 140 of a 0.4-mm thickwater-soaked paper towel having about the same thickness as skin. FIG. 2shows the observed rate of absorption of gaseous C0 ₂ into the surfaceof the towel, i.e., a monotonic quasi-exponential approach of theabsorbed gas volume to the amount apparently required to saturate thewater in the towel with C0 ₂. The near linearity of the second(logarithmic) plot in FIG. 2 shows that the volume of gas changesquasi-exponentially as saturation is approached. The observed initialrate of absorption determined from several such tests fell in the range0.6-1.2 ml/min, and saturation occurred at 4-10 ml, for the 80-cm² areatest surface. If the vascular bed of the skin suppresses saturation byremoving C0 ₂ as fast as it diffuses into the skin, these rates wouldsuggest that a 100-200 cc transcutaneous dose C0 ₂ would be delivered in1½ to 5½ hours. The inventors thus concluded that the rate wassufficient for a “CO₂ patch” to be feasible. Significantly, the timeconstant for the exponential saturation was found to be about three tofive minutes, which was about the same as the reported time fordisappearance of the gas emphysemum in the previously describedsubcutaneous gaseous C0 ₂ injections.

[0038] Finally, as shown in FIG. 3, an attempt was made to measure therate of transcutaneous absorption of C0 ₂ into a human body using thesame system. An area of skin on the right anterior thigh sufficientlylarge for two positions of the funnel 120 applicator was washedthoroughly and soaked with water for fifteen minutes. The funnel 120 waspurged of air by prolonged C0 ₂ flow (for about 10 minutes) while seatedon the wet skin in the upper thigh position 160, and then was slid tothe lower thigh position 170 at zero time. In several such tests, eachover a period of about 10 minutes, no significant flow was observed,which suggested that there was no measurable absorption of C0 ₂ by theskin within the sensitivity of the method. In other words, it appearedthat less than <0.1 ml of gas was absorbed. However, after all suchtests, when the funnel 120 containing C0 ₂ was removed, a hyperemia wasobserved over the region of skin in contact with C0 ₂, corresponding tothat of moderately severe sunburn. This reddening requires about threeto five minutes to develop in contact with C0 ₂, and a similar period tosubside after removal of the C0 ₂. There were no observed aftereffects.In a control experiment, the inventors found that no reddening of theskin appeared when only air was applied for ten minutes. Therefore, theinventors concluded that some quantity of C0 ₂, sufficient to cause theobserved vascular effects, must have diffused into the skin. Therefore,the inventors continued with their experiments to determine if atranscutaneous application of C0 ₂ would reduce local pain.

[0039] Application of Capnic Solutions

[0040] Treatment of Pain by Transcutaneous Infusion of CO₂

[0041] To determine if pain could be treated using gaseous C0 ₂, a73-year-old female subject was selected, who was diagnosed withfibromyalgia. The subject was experiencing chronic, highly localizedpain over an area of approximately two to three centimeters in diameteron both her outer thighs. The area was exquisitely sensitive to touch.In addition to the localized pain, the subject also had more generalpain along the path of the sciatic nerve which occurred identically inboth legs.

[0042] The experiment employed an open-cylinder procedure shown in FIG.4. The interior diameter of the cylinder 410 measured approximately 5cm. The cylinder was placed over the area of localized pain on one thigh420. The cylinder was then filled approximately 2 cm deep withcarbonated water 430. After the application of carbonated water 430, thearea of application was observed to be reddened to the degree describedabove in the Preliminary Experiments section when gaseous C0 ₂ wasapplied to the skin. In this experiment a PVC pipe was used as thecylinder, although in practice other materials could be used, providedthat the resulting device was able to hold the water in position overthe treatment area for the desired time.

[0043] The subject stated, within 2-3 minutes after the application ofthe carbonated water, that the localized pain was fully relieved, andthat the general pain was partially suppressed over about a 15-cm lengthalong the sciatic nerve path in her thigh. The pain in the other leg wasnot affected. The device was then removed from the subject's thigh.About 1½ hour after the application, the subject stated that thelocalized pain had returned somewhat, but still was far less than thatin the other leg. The general pain then was about the same in both legs.

[0044] In part as a result of the foregoing experiment, the inventorsbelieve that carbonated water baths may be used effectively fortreatment of musculoskeletal, neural and other rheumatic pains byimmersion of the affected portions of the body or the whole body intofresh carbonated water for at least three minutes.

[0045] Treatment of Allergic Rhinitis by Transmucosal Application ofCapnic Nasal and Oral Spray

[0046] Because of the observed similarity of the physiological effectsof gaseous C0 ₂ and a capnic solution (carbonated water) applied to theskin, the inventors believed that a capnic solution might be effectivefor treatment of upper respiratory indications for which infusion ofgaseous C0 ₂ is effective. With reference to FIG. 5, to test thishypothesis, a 70-ml commercially marketed plastic “squeeze” bottle 510for dispensing a physiological saline spray was ¾ filled with fresheffervescing carbonated water. The carbonated water spray was thensprayed into the nose of a subject 520 who was suffering a mild allergicrhinitis attack. The inflammation and allergic distress were relievedimmediately in a manner similar to that found when gaseous C0 ₂ wasinfused into the subject's nose. During the course of a day as allergicrhinitis attacks reoccurred, the carbonated water spray and gaseous C0 ₂infusion were used alternately and their relative effectivenessassessed. The subject concluded that the two methods of treatment wereequally effective for relief and suppression of allergic rhinitissymptoms.

[0047] Other subjects tried the spray once and also found it to giveeffective treatment. Those subjects resisted its further use, however,because all subjects found that the spray injection treatment is highlydisagreeable compared with the gas infusion treatment and is no moreeffective. The disagreeable aspects cited were the discomfort associatedwith a liquid being sprayed up the nose and the messiness of theeffluent liquid from the nose after the spray. Nevertheless, thecarbonated nasal spray is a distinct alternative for treatment of theupper respiratory distress indications, and shares many of theadvantages of a gaseous C0 ₂ infusion treatment including effectiveness,ease of use, rapid relief on demand, unlimited dose, low cost, andfreedom from aftereffects and other contraindications associated withthe use of drugs. It is also possible to use the carbonated spray orallyto deliver the dose of carbon dioxide to the mucous membranes in asimilar manner.

[0048] The carbonated spray may offer superior treatment for patientssuffering from dry nasal membranes along with allergy symptoms, i.e.,the conditions for which the several saline nasal spray productspresently are marketed. As with those products, a buffered isotonicsolution should be used to minimize tissue volume changes by osmosis,but the solution should be carbonated by dissolving the maximum amountof C0 ₂ in it that is consistent with a practical operating pressure.The inventors found that the degree of carbonation of commerciallymarketed carbonated water corresponds to an acceptable C0 ₂ pressure inthe spray bottle (1-2 lb/in² at room temperatures). Furthermore, it hasbeen found that the carbonated water can be stored for an indefinitelylong period when the screw cap (not shown) of the dispenser 510 istightly closed. Multiple effective doses of the spray are obtained untilalmost complete exhaustion of the spray bottle contents.

[0049] Measurement of the Electrical Potential Accompanying theTranscutaneous Application of a Capnic Solution

[0050] With reference to FIG. 6, the inventors also undertook anexperiment to obtain a quantitative indication of the extent and effectof transcutaneous infusion of C0 ₂ effected by applying a capnic aqueoussolution (carbonated water) to the skin. In this experiment theinventors used a cylinder 605 of about 5 cm interior diameter, similarto that shown in FIG. 4, to apply about 2 cm of the capnic solution 610to a subject's anterior thigh 620. The inventors then measured, using adigital logger 650, the resulting electrical potential differencebetween the liquid and the subject's body. As shown in FIG. 6, thepotential difference was measured between a stainless steel electrode630, immersed in a liquid pool (e.g. capnic solution) applied to theskin of the anterior thigh, and a large (15×25 cm) aluminum plate 640(as indifferent electrode) applied to the moistened skin of theposterior thigh 620.

[0051] In all tests a hyperemia occurred over the area of contactbetween the skin and the applied pool of carbonated water. The skin wasreddened to about the same degree and within about the same time ofthree to five minutes as was described in connection with theapplication of gaseous C0 ₂ to the skin. In control experimentscomprising application of distilled water to the subjects' skin suchreddening did not occur. Therefore, the inventors concluded that thehyperemia occurred as a result of C0 ₂ infusion into the skin.

[0052] FIGS. 7-9 show the changes in body/liquid potential differenceafter distilled water and carbonated water were applied simultaneouslyto adjacent regions of the skin of the anterior thigh. Both carbonatedwater and distilled water electrodes are spontaneously positive relativeto the body electrode, i.e., such as to inhibit transport of carbonateor bicarbonate ions into the body from the capnic solution, or to expelthem from the body into the distilled water.

[0053] Many observations have shown that the carbonated water potentialand its change with time always are substantially greater than those fordistilled water and that the changes are approximately equal to the cellresting potential (60-90 mv). Furthermore, as can be seen in FIG. 7, thepotential is directly related to the concentration of the carbonatedwater (the “stale” solution shows no bubbles while the “fresh” solutioneffervesces and deposits bubbles onto the skin). There was an increasein potential when the carbonated water was agitated which suggests thatthe decrease in potential with time arises in part from a C0 ₂concentration gradient in the carbonated water. No change occurs whenthe distilled water is agitated.

[0054] The decrease in carbonated water potential with time can arisefrom a decrease in its C0 ₂ concentration due to C0 ₂ diffusion into theskin, from a concentration gradient within the solution, and from anincrease in the C0 ₂ concentration in the skin. The increase inpotential upon agitation of the solution indicates that diffusion isprimarily into the skin rather than into the atmosphere. Although notshown here, the C0 ₂ dose into the skin can be determined as a functionof the decrease in the concentration of C0 ₂ in the agitated solution byvarious methods of measurement (e.g., conductivity, cell potential, pHor titration). By correlation of such measurements with the observeddecrease in liquid/body potential, that decrease could be used as aconvenient clinical method for dose determination.

[0055] The changes in distilled water potential can arise from changesin concentration of body fluids in the skin and in the applied liquiddue to interdiffusion of the distilled water and the body fluidcomponents, for example, by osmosis.

[0056]FIG. 8 shows data taken under the same conditions as those in FIG.7 except that they are taken immediately after exercise. It can be seenthat the potentials and associated changes with time are more than twiceas large as those in FIG. 7. The data in FIG. 9, taken 15 minutes afterthose in FIG. 8, show a reversion to the behavior observed beforeexercise in FIG. 7. In addition, it can be seen that the application ofC0 ₂ actually decreases the potential of the liquid applied on the skinin an adjacent region, whether that liquid is carbonated or distilledwater. summary of the results of many such tests:

[0057] 1. The liquid/body potential difference appears to be aquantitative measure of the concentration and delivered transcutaneousdose of C0 ₂ via carbonated water applied to the skin.

[0058] 2. The ˜3 minute exponential decay time of the liquid/bodypotential changes corresponds to the time for reddening of the skin byapplied C0 ₂ and for the reddening of the skin to disappear, suggestinga 1:1 correlation of the observed potential and the physiologicaleffects of C0 ₂ application.

[0059] 3. Other factors affecting the underlying muscle, such asexercise, affect the liquid/body potential.

[0060] 4. After the initial topical application of carbonated water,subsequent applications of carbonated water to the skin in one region ofan underlying muscle affects the liquid/body potential in adjacent andnon-adjacent regions of that muscle, suggesting that the effects oftranscutaneous infusion of C0 ₂ are not confined to the skin in theimmediate region of application.

[0061] The inventors conclude that a possible explanation for theobserved results of the experiments described above is that theapplication of C0 ₂ to the skin changes the local electrical potentialthrough a response of the local and adjacent tissue in opposition to anincrease in the local physiological concentration of C0 ₂. Thisconclusion is supported by the observed reduced absorption of C0 ₂ in aphysiologically active tissue, shown in FIG. 3, as compared with that inan equivalent passive system as shown in FIG. 2. This proposed mechanismis confirmed by the observed development of an electrical potential inopposition to the transport of carbonate and bicarbonate ions into thetissue as shown in FIGS. 7-9, and by the increase in this reactionpotential due to increased partial pressure of C0 ₂ in the tissueresulting from exercise as shown in FIG. 8. Whatever the actualmechanism, the response to the application of C0 ₂ apparently isassociated with a reduction of pain in the local and adjacent region ofC0 ₂ application.

[0062] Implications for Therapeutic Use of CO₂

[0063] Gaseous C0 ₂

[0064] In therapeutic use, a subject would apply gaseous C0 ₂ to anaffected area of the body. Application could be accomplished by a numberof different apparatus. In the simplest application shown in FIG. 10, adispensing device 1000 such as that shown in U.S. patent applicationsSer. Nos. 09/614,389 and 09/708,186 for infusion of the nose, mouth oreyes could be used to bathe the affected area in C0 ₂. The flow rate forthe devices of U.S. patent application Ser. No. 09/614,389 is as low as2 to 10 cc/sec, although higher flow rates are possible with the samedevice. As shown in FIG. 10, the user could place a hand 1010 over thearea forming a pocket between the hand and the area of skin. By infusingthe CO₂ into the pocket, the rate at which the CO₂ is dispersed into thesurrounding air will be reduced. Alternatively, as shown in FIG. 11, acup 1100 or similar apparatus of appropriate size and shape could beused in conjunction with the source of CO₂ 1110 to retain the gas overthe treated area. Preferably, the cup would be of a gas impermeablematerial to limit the loss of CO₂. Of course, the funnel apparatus usedin the inventors' experiment to measure the rate of transcutaneousabsorption of C0 ₂ could also be used with minimal modifications toaccomplish the same purpose. With the cup or funnel, after placement onthe affected area, the cup or funnel would be purged of air by aprolonged flow of CO₂. Unlike the experiment described previously, itwould not be necessary to move the device after the purging procedure.The time of CO₂ application could vary from a few minutes to, if anattached cup or funnel device was used, a few hours.

[0065] The gas used for treatment should be essentially pure, that is,by volume, at least 50% carbon dioxide, preferably at least 70% carbondioxide and more preferably 95% or greater. For certain applications,gases other than CO₂, drugs, surfactants or other substances could beincorporated into the flow.

[0066] Aqueous Solutions of CO₂

[0067] As suggested above, an aqueous solution of C0 ₂ can be used torelieve both localized and general pain through submersion of theaffected areas. As shown in FIG. 12, the general procedure would be toplace fresh, carbonated water (not shown) into a container or tub 1200of appropriate size and have the subject submerge the area(s) to betreated in the carbonated water, for example, the hand and wrist 1210.The subject could vary the time of submersion from a few minutes,preferably at least three minutes, to a few hours, depending upon theseverity of the pain and individual response to the treatment.Submersion of the whole body or substantially the whole body, i.e., theentire body except the head to allow for breathing, may be appropriatefor certain treatments.

[0068] As an alternative, which is shown in FIG. 4, depending upon thesize and location of the treated area, a device such as that used totest the subject response could be used. In other words, the fresh,carbonated water 430 could be contained in a CO₂ “ patch,” for examplean open container or cylinder 410, and the container placed on the skinover an affected area.

[0069] For application to mucous membranes, such as the nose, mouth orears, as shown in FIG. 5 the fresh carbonated water can be placed in astandard “squeeze” bottle 510, such as is used for nasal spray, or amodification thereof. To use, the subject would open the bottle, placedthe bottle into a nostril or other orifice, and squeeze to produce aspray of the capnic solution. The bottle would then be closed tightly topreserve the carbonated water for later use.

[0070] CO₂ Patches

[0071]FIG. 13 shows “patch” embodiments by which CO₂ or other gaseousagents can be applied to the skin to relieve pain in a region of thebody. FIG. A shows a patch 1300 with a peelable closure 1305 to containand protect its active contents before use. FIG. B shows the patch 1300with the peelable closure removed and applied to the skin to relievepain in a region of the body. The patch 1300 consists of a cavity 1310enclosed by a gas and liquid impermeable plastic envelope 1320 having anadhesive rim 1330 for attachment of the edge of the cavity to the skin1335, thereby forming a gas-tight seal and chamber 1340. The chamber1340 is filled with a sponge or other liquid-containing medium 1350soaked with a gas-containing liquid. When the patch is in use thisliquid is in contact with the skin and delivers a dose of the dissolvedgaseous agent to the underlying tissue by transcutaneous diffusion asdescribe herein.

[0072] An electrode 1360 can be used to monitor the dose and its effecton the tissue by measurement of the electrical potential between thiselectrode and a conventional ECG electrode (not shown) elsewhere on thebody, as described and shown in connection with FIGS. 7-9. Although anelectrode as shown could be included for use in a clinical setting, itneed not be a part of a patch intended solely for more general use.

[0073] As an alternative to the liquid containing medium 1350, the patch1300 shown in FIGS. A and B the gas-containing liquid in the chamber1340 can be replaced by an agent that generates the gas by a chemicalreaction such as a mixture of solid citric acid and water-containingmicrocapsules, which when crushed together release a substantialquantity of carbon dioxide gas that then can diffuse through the skin asdescribed. To facilitate diffusion of the gas from the chamber 1340 intothe skin in this embodiment it is desirable to wet the skin beforeapplication of the patch or otherwise before the gas is applied to theskin. As shown in FIG. C, as an alternative to microcapsules, thechamber 1340 may include a porous envelope 1345 inside the gas andliquid impermeable envelope 1320 that contains the gas-generating agent1355 to which water is added just prior to application of the patch 1300to activate the gas generation process. In this alternative, the skinwould not need not be moistened prior to use of the patch.

[0074] In the patch embodiment shown in FIG. D, a small cylinder 1370containing the gaseous agent at low pressure is attached to the patch1300 with a mechanism and port 1375 for its slow release into the patchchamber 1340. In this case it is necessary to provide a vent 1380 forescape of air as air is purged from the patch and to preventoverpressure within the chamber. Such a vent may be desirable in patchembodiments that utilize an agent for chemical generation of the gas. Inthe embodiment shown in FIG. D, it is desirable for the skin to bemoistened prior to application of the patch to facilitate diffusion ofthe gaseous agent into the skin. As an alternative to moistening theskin with water prior to application, the chamber 1340 could be filledwith a carbonated or plain water-soaked sponge or similar medium similarto the medium 1310, and gas from the attached cylinder would then usedto maintain a high gas concentration in the water for long-termapplication.

[0075] The quantity of CO₂ required to achieve saturation of the skin isvery small, so the required volume of carbonated water or gas-generatingagent in the patch, or of gas in the cylinder, is easily contained in aconveniently-sized patch.

[0076] While preferred embodiments of the present invention aredescribed above and in the following claims, it is contemplated thatvarious modifications may be made without departing from the spirit andscope of the invention. Furthermore, many of the features of the variousembodiments described herein can be combined or added to other devicesto obtain the optimum combination of features for particularapplications and markets.

What is claimed is:
 1. A method for transcutaneous delivery of carbondioxide to an individual comprising: Selecting a portion of theindividual's skin; Establishing an environment of essentially puregaseous carbon dioxide; and Placing the selected portion of theindividual's skin in the environment.
 2. A method for transcutaneousdelivery of carbon dioxide as in claim 1 where the establishing stepfurther comprises the steps of: Cupping a hand over the selected portionof skin to form a pocket between the hand and the portion of skin; andDirecting a flow of carbon dioxide into the pocket.
 3. A method fortranscutaneous delivery of carbon dioxide as in claim 1 where theestablishing step further comprises the steps of: Placing a containerover the portion of skin, wherein said container includes an interiorchamber suitable for containing a selected amount of carbon dioxide, anopening communicating with the chamber, such that the opening of thecontainer is over the portion of skin; Purging the container of ambientair; and Directing a flow of carbon dioxide into the container.
 4. Amethod for transcutaneous delivery of carbon dioxide as in claim 1wherein the selecting step further comprises: selecting a portion ofskin adjacent to an area of the individual's body that is experiencingpain.
 5. A device for transcutaneous delivery of carbon dioxidecomprising: A source of carbon dioxide under pressure; A container,further comprising a chamber for containing a selected amount of gaseouscarbon dioxide, and defining at least one opening communicating with thechamber adapted to be placed on a portion of an individual's skin, andat least one opening in communication with the chamber adapted toreceive a flow of carbon dioxide; and a flow regulator attached to thesource of carbon dioxide for generating and controlling a flow of carbondioxide and adapted for connection to the at least one opening adaptedto receive a flow of carbon dioxide.
 6. A device as in claim 5, whereinthe container further comprises a funnel.
 7. A device as in claim 5,wherein the container further comprises a flexible cup.
 8. A method fortranscutaneous delivery of carbon dioxide to an individual comprisingthe steps of: Selecting a portion of the individual's skin; and Applyinga quantity of carbonated water to the selected portion of theindividual's skin.
 9. The method of claim 8, wherein the applying stepfurther comprises submerging the selected portion of the individual'sskin in the carbonated water.
 10. The method of claim 8, wherein theapplying step further comprises the steps of: Placing a selectedquantity of carbonated water in a container that defines an opening,said opening adapted to be sealed against the selected portion of theindividual's skin; and Placing the opening over the selected portion ofthe individual's skin and orienting the container such that thecarbonated water contacts the selected portion of the individual's skin.11. The method of claim 9, wherein the applying step further comprisessubmerging the selected portion of the individual's skin in thecarbonated water for at least three minutes.
 12. The method of claim 10,wherein the applying step further comprises applying the carbonatedwater to the selected portion of the individual's skin for at leastthree minutes.
 13. The method of claim 8, wherein the container is largeenough to receive substantially all of the individual's body, andwherein the selected portion of the individual's skin comprisessubstantially all of the individual's transcutaneous skin surface, andthe applying step further comprises: Submerging the selected portion ofthe individual's skin in the carbonated water.
 14. The method of claim13, wherein the applying step further comprises, submerging the selectedportion of the individual's skin for at least three minutes.
 15. Amethod for transcutaneous delivery of carbon dioxide as in claim 8wherein the selecting step further comprises: selecting a portion ofskin adjacent to an area of the individual's body that is experiencingpain.
 16. A method for transcutaneous delivery of carbon dioxide as inclaim 8 wherein the applying step further comprises: Placing a selectedquantity of carbonated water in an absorbent material; and Placing theabsorbent material against the selected portion of the individual'sskin.
 17. A method for transcutaneous delivery of carbon dioxide as inclaim 16 wherein the applying step further comprises placing theabsorbent material against the selected portion of the individual's skinfor at least three minutes.
 18. A device for transcutaneous applicationof carbon dioxide comprising: A gas impermeable sheet defining aperimeter and further comprising an adhesive placed around theperimeter, adapted for removable application to a subject's skin, toform a pocket between the subject's skin and the sheet; An absorbentmedium containing a carbon dioxide containing liquid, adapted to beplaced inside the pocket; Whereby the absorbent medium and the liquidmay be placed against a subject's skin and held within the sheet todeliver a dose of carbon dioxide to the subject.
 19. A device as setforth in claim 18 further comprising: A vent in the sheet.
 20. A deviceas set forth in claim 19 further comprising: A port adapted forattachment to a source of carbon dioxide.
 21. A device fortranscutaneous application of carbon dioxide comprising: A gasimpermeable sheet defining a perimeter and further comprising anadhesive placed around the perimeter, adapted for removable applicationto a subject's skin, to form a pocket between the subject's skin and thesheet; A port adapted for attachment to a source of carbon dioxide, incommunication with the pocket; Whereby carbon dioxide may be placedwithin the pocket and in contact with the subject's skin to deliver adose of carbon dioxide to the subject.
 22. A device as set forth inclaim 21 further comprising: A vent in the sheet.
 23. A device as setforth in claim 18 further comprising an electrode extending through thesheet, in contact with the carbon dioxide containing liquid and adaptedfor connection to an external meter.
 24. A device for transcutaneousapplication of carbon dioxide comprising: A gas impermeable sheetdefining a perimeter and further comprising an adhesive placed aroundthe perimeter, adapted for removable application to a subject's skin, toform a pocket between the subject's skin and the sheet; An activatablesource of carbon dioxide, adapted to be placed inside the pocket;Whereby, when activated, the source of carbon dioxide releases carbondioxide into the pocket, in contact with the subject's skin, to delivera dose of carbon dioxide to the subject.
 25. A device as set forth inclaim 24 further comprising: A vent in the sheet.
 26. A method fortransmucosal delivery of carbon dioxide to an individual comprising thesteps of: Placing a quantity of carbonated water into a container fromwhich a spray of carbonated water may be generated; and Spraying aquantity of carbonated water to a selected mucous membrane.
 27. A methodfor transmucosal delivery of carbon dioxide as set forth in claim 26wherein the selected mucous membrane is the mouth.
 28. A method fortransmucosal delivery of carbon dioxide as set forth in claim 26 whereinthe selected mucous membrane is the nose.